The immune system and morphine dependence.
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Animals↗
Biomedical subjects
P M Dougherty
Publications and source records attributed to P M Dougherty.
Immune response products alter CNS activity: interferon modulates central opioid functions.
The present report provides evidence to support the hypothesis that peptides released during an immune response alter CNS activity and thus may provide a means for the immune system to transmit afferent signals into the brain. Specifically, it is demonstrated that recombinant interferon-alpha (rIFN-alpha), a peptide associated with the immune response to viral infection, can alter opiate withdrawal severity in a dose-dependent manner upon direct injection into brain areas essential for this phenomenon. These results are compared and contrasted with the effect of systemically injected rIFN-alpha upon opiate withdrawal. In addition, an electrophysiological investigation into the basis of the interaction of opioids and rIFN-alpha in brain structures essential for the expression of opioid activities is also presented. Finally, the effects of rIFN-alpha upon the functions of both the CNS and other systems is discussed in terms of the effects reported for other peptides associated with immune responses.
Animals↗
Neuroimmune intercommunication, central opioids, and the immune response to bacterial endotoxin.
Muramyl dipeptide is the smallest biologically active fragment of the lipopolysaccharide (LPS) moiety of gram-negative bacteria cell walls. The present report demonstrates that this product, associated with the immune response to bacterial infection, can modify CNS activity. Specifically, it is demonstrated that 6-0-stearoyl-muramyl dipeptide (MDP) can attenuate opiate withdrawal severity in a dose-dependent fashion when injected directly into areas of the brain essential for this phenomenon. In addition, MDP alters both baseline and postnarcotic electrophysiologic responses of four brain areas essential for various opioid activities. Similar findings have been reported for interferon-alpha (IFN-alpha), a peptide associated with the immune response to virus. Yet, even though MDP and IFN are shown to exert similar effects on opioid activity, there are also some very distinct differences in the actions of both of these immune response products. These observations suggest that central opioid systems may provide targets for the perception as well as the differentiation of afferent immunologic sensory input to the brain.
Acetylmuramyl-Alanyl-Isoglutamine↗
Cyclosporine affects central nervous system opioid activity via direct and indirect means.
It is demonstrated that cyclosporine (CsA), a novel fungal-derived immunosuppressive agent, attenuates naloxone-precipitated morphine withdrawal in an unusual dose-dependent manner following direct intracerebroventricular (icv) administration. However, comparison and contrast of this effect of CsA following icv versus ip administration demonstrates that although CsA does alter the severity of withdrawal by a direct effect within the CNS, the agent is most effective when given systemically. It is also demonstrated that CsA alters the electrophysiologic properties of discrete brain nuclei both when given alone and when given concomitant with morphine and naloxone.
Animals↗
Evidence of an immune system to brain communication axis that affects central opioid functions: muramyl peptides attenuate opiate withdrawal.
Muramyl peptides are metabolic breakdown products of bacterial cell walls formed in vivo by the reticuloendothelial system. These agents have a variety of immune modulatory and neuropharmacologic effects. It has previously been demonstrated that a variety of immune modifying agents can induce alterations in certain behaviors elicited by opiates. In the present study we investigate possible reciprocal interactions between muramyl dipeptides (MDPs) and central opioid systems using three different experimental models: (1) naloxone-precipitated withdrawal behavior in morphine-dependent rats; (2) the tail immersion assay for determination of morphine-induced antinociception and (3) rectal temperature measurement of the pyrogenic activity of MDP. It is shown that two derivatives of MDP attenuate the severity of naloxone-precipitated withdrawal and morphine-induced antinociception. In addition, it is demonstrated that the pyrogenic activity of a stearoyl derivative of MDP is altered by chronic morphine treatment. These findings suggest both novel neuropharmacologic properties of muramyl dipeptides, as well as demonstrate that yet another immune modifier interacts with centrally mediated opioid phenomena.
Acetylmuramyl-Alanyl-Isoglutamine↗
Participation of lymphoid cells in the withdrawal syndrome of opiate dependent rats.
Treatment of rats with 500 Rads whole-body ionizing irradiation prior to chronic administration of morphine reduced the severity of the naloxone induced withdrawal signs. In contrast, adoptive transfer of 2-6 X 10(8) lymphoid cells to irradiated rats prior to chronic morphine treatment completely restored the ability to manifest the withdrawal signs precipitated by naloxone. These observations offer the possibility that the immune system participates in opiate addiction.
Animals↗
Irradiation exposure modulates central opioid functions.
Exposure to low doses of gamma irradiation results in the modification of both the antinociceptive properties of morphine and the severity of naloxone-precipitated withdrawal in morphine-dependent rats. To better define the interactions between gamma irradiation and these opiate-mediated phenomena, dose-response studies were undertaken of the effect of irradiation on morphine-induced antinociception, and on the naloxone-precipitated withdrawal syndrome of morphine-dependent rats. In addition, electrophysiologic studies were conducted in rats after irradiation exposure and morphine treatment correlating with the behavioral studies. The observations obtained demonstrated that the antinociceptive effects of morphine as well as naloxone-precipitated withdrawal were modified in a dose-dependent manner by irradiation exposure. In addition, irradiation-induced changes in the evoked responses obtained from four different brain regions demonstrated transient alterations in both baseline and morphine-treated responses that may reflect the alterations observed in the behavioral paradigms. These results suggest that the effects of irradiation on opiate activities resulted from physiologic alterations of central endogenous opioid systems due to alterations manifested within peripheral targets.
Animals↗
Differential modification of morphine and methadone dependence by interferon alpha.
Subcutaneous implantation of a pellet of methadone was presented as a novel method for the establishment of physical dependence upon this agent and it was compared to (1) the state of physical dependence induced by multiple injections of methadone, administered over several days, and (2) the dependence established by injections of morphine and the implantation of a morphine pellet. Comparable signs of drug dependence were observed in rats treated with both morphine and methadone following the administration of the opiate antagonist naloxone. The administration of interferon-alpha significantly attenuated the severity of the withdrawal syndrome in dependent rats after chronic exposure to morphine and to a lesser extent after morphine and methadone in combination. In contrast, alpha interferon did not affect 6 of the 7 abstinence signs in animals dependent upon methadone alone. The observations suggest that the states of physical dependence upon morphine and methadone may be separate phenomena that involve different physiological mechanisms. Thus, interferon may be a useful adjunct in the treatment of subjects dependent upon morphine but not in those dependent on methadone.
Animals↗
Evidence of neuro-immunologic interactions: cyclosporine modifies opiate withdrawal by effects on the brain and immune components.
The capacity of the immune system to participate in processes primarily considered to be central nervous system (CNS) phenomena has been suggested recently by several studies demonstrating the ability of various immune modifiers to attenuate opiate withdrawal severity. The present study demonstrates that within 2 h after injection, the immune modifier cyclosporine A (CsA) has the ability to attenuate the opiate withdrawal syndrome precipitated by naloxone in morphine-dependent animals. Furthermore, it is demonstrated that this effect of CsA can be adoptively transferred by splenic mononuclear cells from immune-modulated (CsA-treated) donors into morphine-dependent recipients. However, unlike direct injections of CsA, CsA-treated immune components require at least 24 h to achieve their full attenuating effect upon withdrawal severity. Since opiate withdrawal behavior is predominantly a CNS-mediated phenomenon, these observations suggest both direct effects of CsA on the brain as well as the participation of immune components in the opiate withdrawal syndrome. This finding lends further support to the hypothesis that immune components have the ability to modulate central nervous system activities in a neuro-immunologic axis of communication.
Animals↗
Physiology and genetics of tree growth response to moisture and temperature stress: an examination of the characteristics of loblolly pine (Pinus taeda L.).
Water stress and temperature impose fundamental limits to forest productivity. Stresses caused by fluctuating or extreme temperatures or limited water availability vary both seasonally and from year to year. The role of these stresses should be considered when investigating the causes of declines in forest productivity. Forest growth, or carbon gain, can be related quantitatively to three components: leaf area, rate of net photosynthesis and rate of respiration. This paper examines effects of temperature and water supply on these components with particular reference to loblolly pine (Pinus taeda L.), a species of economic importance in the southeastern United States where declines, of unknown cause, in forest productivity have been reported.
Journal Article↗
The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance.
An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids.
Animals↗
Opiate antinociception is altered by immunemodification: the effect of interferon, cyclosporine and radiation-induced immune suppression upon acute and long-term morphine activity.
It has recently been demonstrated that various forms of immune modification result in a profound attenuation of the opiate withdrawal syndrome. Herein we investigate the extent to which some of the immune modifiers active in withdrawal attenuation affect other opiate related behaviors, namely antinociception and the development of tolerance to this effect. The observations demonstrate that immune modification by cyclosporine and irradiation exposure result in an alteration of the acute antinociceptive effect of morphine; while none of these treatments modify the development of tolerance to this property of morphine.
Animals↗
Net Photosynthesis and Early Growth Trends of a Dominant White Oak (Quercus alba L.).
Examination of the relationship between photosynthesis and growth of a dominant white oak (Quercus alba L.) tree has shown that most growth processes were either completed or well underway before the establishment of significant positive rates of net photosynthesis. Growth was initiated first in the root system (March 3), followed by stem cambial growth (March 26) and later by flower, leaf, and branch growth (April 10). During the period of rapid leaf and branch growth, root and cambial growth ceased and then resumed as the leaves approached maturity. The rapid rate of leaf maturation, the early appearance of positive rates of net photosynthesis in leaves (15% of final size) and the CO(2)-refixing capability of elongating branch tissue reduced the period of time that this white oak tree was dependent on stored reserves. Lower temperature optima and compensation points in developing leaves and stems indicated that the growth-temperature response was optimized for the lower seasonal temperatures observed during the spring. This temperature adaptation further reduced the time that this tree was dependent on stored reserves.
Journal Article↗
Reflection spectra of small paint samples: a potential solution.
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Accidents, Traffic↗
Report on two early United States firearms identification cases.
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Forensic Medicine↗
Neural changes in acute arthritis in monkeys. I. Parallel enhancement of responses of spinothalamic tract neurons to mechanical stimulation and excitatory amino acids.
Somatosensory neurons of the spinal cord, including projection neurons, become hyperexcitable to mechanical stimuli during the development of experimental arthritis in rats and cats and hence are suggested to participate in the generation of arthritic hyperalgesia in humans. The experiments described here show a potentiation of the responses of spinothalamic tract (STT) neurons in monkeys during the development of an acute arthritis. The results demonstrate that the responses of STT neurons to mechanical stimuli and to iontophoretically applied excitatory amino acids (EAAs), particularly those acting at non-N-methyl-D-aspartate (non-NMDA) receptors, become enhanced during the development of inflammation produced by intra-articular injection of kaolin and carrageenan. Since the enhancement of both responses follows a similar time course, the results of this work suggest a role for EAAs in the hyperalgesia associated with arthritis and hence may provide a possible pharmacologic target for alleviation and/or prevention of arthritic pain.
Acute Disease↗
Neural changes in acute arthritis in monkeys. II. Increased glutamate immunoreactivity in the medial articular nerve.
Glutamate and other excitatory amino acids have been shown to play a key role in nociception and the hyperalgesia associated with the acute inflammatory response. In an effort to understand more fully the role of Glu in this process, we determined that there is Glu in a percentage of axons in the medial articular nerve (MAN) of monkeys, a source of preterminal afferent fibers innervating the knee joint. After induction of the experimental knee joint inflammation with a kaolin/carrageenan mixture, comparison was made of the percentage of Glu positive axons in the MAN on the side of the inflammation versus the contralateral MAN using post-embedding immunogold electron microscopic methods. A doubling in the percentage of Glu-containing axons was observed on the side of the experimental arthritis as compared to the MAN of the other side or of uninjected controls. Glu positive axons were unmyelinated or were included in the small, thinly myelinated group in control nerves. Following induction of the inflammation, axonal diameter measurements revealed an increase in Glu content primarily in the small, thinly myelinated axons, which correspond to the group III afferent fibers. These increases were observed in the anesthetized preparation only when injection of kaolin/carrageenan was combined with joint flexion and mechanical stimulation. The dramatic increase in percentages of fibers stainable for Glu in the MAN following the induction of inflammation suggests that Glu content is greatly increased in the afferent fibers and may be a major contributor to the enhanced responses of sensory neurons in inflammatory states such as arthritis.
Acute Disease↗
Neural changes in acute arthritis in monkeys. III. Changes in substance P, calcitonin gene-related peptide and glutamate in the dorsal horn of the spinal cord.
The effects of an experimentally induced arthritis on immunoreactivity of putative primary afferents neurotransmitter/neuromodulators were examined. Immunoreactive staining for substance P (SP), calcitonin gene-related peptide (CGRP) and glutamate (Glu) in the monkey dorsal horn was examined following inflammation of one knee joint induced by injection of 5% kaolin and 5% carrageenan. Spinal cords were examined at different time periods after induction of arthritis (2.5, 4, 6 and 8 h). Side to side differences in immunoreactivity were determined by a computer assisted quantitation system. A significant overall decrease in immunoreactivity of the lumbar versus the cervical dorsal horn was found for SP. The decrease for SP showed maximal changes of 68.3% at 4 h and 54.7% at 6 h. Immunoreactivity for CGRP was decreased 31.5% at 8 h and variable at other time points. Immunoreactivity for Glu, showed an ipsilateral increase of 31.4% at 4 h, 33.7% at 6 h, 39.9% at 8 h and a significant effect for lumbar versus cervical. Repetitive peripheral stimulation of the joint was shown to be important for changes in SP and Glu immunoreactivity. Without frequent peripheral stimulation in the early stages of the development of arthritis, SP showed no quantitative side to side differences. Increases in Glu immunoreactivity were present but not as prominent with minimal joint manipulation. These studies suggest that Glu may be involved in the aching pain of inflammation at rest whereas SP, CGRP and Glu may mediate pain induced by joint movement.
Acute Disease↗